Study Evaluating the Safety and the Efficacy of Human T Lymphoid Progenitor (HTLP) Injection to Accelerate Immune Reconstitution After Umbilical Cord Blood (UCB) Transplantation in Adult Patients With Hematologic Malignancies (HTLP-ONCO) (HTLP-ONCO)

A Phase I/II Study Evaluating the Safety and the Efficacy of Human T Lymphoid Progenitor (HTLP) Injection to Accelerate Immune Reconstitution After Umbilical Cord Blood (UCB) Transplantation in Adult Patients With Hematologic Malignancies

This is an open-labelled and non-controlled Phase I/II clinical trial, evaluating the safety and the efficacy of Human T Lymphoid Progenitor (HTLP) injection to accelerate immune reconstitution after umbilical cord blood (UCB) transplantation in adult patients with hematologic malignancies. The dose limiting toxicity of HTLP injection will be evaluated using a model-based design.

Study Overview

• Status: Recruiting
• Conditions: Hematologic Malignancy
• Intervention / Treatment: Drug: Human T Lymphoid Progenitor (HTLP) injection

Detailed Description

Allogeneic bone marrow transplantation (AlloSCT) is the treatment of choice for high- risk acute myeloid leukemias in complete first remission after induction therapy and other high-risk hematological malignancies. Umbilical cord blood grafts are frequently used for patients lacking an HLA- matched family donor (Matched-sibling donor, MSD) as well as in the absence of an appropriate unrelated donor (10/10 MUD). As any HSCT, UCB transplantations are associated with the risk of acute and chronic GVHD, post- transplant immunodeficiency with increased risk of infections as well as relapse. Especially the risk of infection and therefore non- relapse mortality (NRM) or transplant- related mortality (TRM) is significantly higher in UCB transplantations as compared to MSD or 10/10 MUD transplantations. All of these risks have been linked to a significant delay in immune reconstitution including various immune cell populations like CD4 and CD8 T cells, Treg, NK, iNKT, pDC and others.

The investigators therefore make the hypothesis that if T-cell-mediated immunity was rapidly generated after a partially HLA-compatible UCB transplantation will reduce the risk of infection and to prevent relapse without increasing the risk of GVHD.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Olivier HERMINE, PhD & MD; Phone Number: +33 144495282; Email: olivier.hermine@aphp.fr

Study Locations

• France
  • Pessac, France, 33604
    • Recruiting
    • Service d'Hématologie et thérapie cellulaire / CHU of Bordeaux
    • Contact: Edouard FORCADE, PhD & MD; Email: edouard.forcade@chu-bordeaux.fr
  • Toulouse, France
    • Recruiting
    • IUCT Oncopole Toulouse
    • Contact: Anne HUYNH, PhD, MD; Phone Number: 05 31 15 71 91; Email: huynh.anne@iuct-oncopole.fr
  • Villejuif, France
    • Not yet recruiting
    • Institut Gustave Roussy
    • Contact: Jean-Henri BOURHIS, PhD MD; Phone Number: 01 42 11 53 82; Email: jean-henri.bourhuis@gustaveroussy.fr
  • Île-de-France
    • Paris, Île-de-France, France, 75015
      • Recruiting
      • Hematology department / Necker Children's Hospital
      • Contact: Olivier HERMINE, PhD & MD; Phone Number: +33 144495282; Email: olivier.hermine@aphp.fr
      • Contact: Felipe SUAREZ, PhD & MD; Email: felipe.suarez@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients (≥ 18 years old and <66 years old) at the time of inclusion and eligible for an allogeneic stem cells transplantation and fit to receive the specified conditioning regimen
• Patients with hematologic malignancies
• Absence of a matched - related sibling donor (MSD) or a matched unrelated donor (MUD) 10/10
• SORROR score compatible with the pre specified conditioning and to discuss with the Principal Investigator
• Presence of two UCB units with the following criteria*: HLA- matched 4/8, 5/8, 6/8, 7/8 or 8/8 for HLA- A, -B, -C and DRB1 loci AND
• Presence of at least one UCB unit with the following criteria*: ≥ 3 x 10e7 TNC/kg or ≥ 1.5 10e5 CD34+/kg pre- freezing * For the UCB taken into HTLP culture, the CD34+ content does not need to meet the above cellularity criteria, as expansion during HTLP culture has been proven to ensure the appropriate number of CD7+ needed for each dose.

The non- cultured UCB will be chosen to have a higher CD34+ cell content in order to enable long- term hematopoietic engraftment

• No treatment with another investigational drug within one month before inclusion
• Patient affiliated to social security
• Written, informed consent of the patient
• Absence of Donor Specific Antibodies (DSA) with a MFI > 5000

Exclusion Criteria:

• Any of the standard contraindications to allogeneic transplant

  • Left ventricular ejection fraction <50%
  • Abnormal biochemistry results (ALT/AST>10xULN, total bilirubin>2.5xULN, creatinin clearance <60ml/min)
• Inability to understand and provide informed consent
• Concomitant infectious disease: HTLV-I, HIV-I or HIV-II
• Pregnancy or breastfeeding for women of childbearing potential
• Patients with progressive hematologic malignancies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Human T Lymphoid Progenitor (HTLP) injection; HTLP cellular product obtained after 7 days of culture of immune-selected CB	Drug: Human T Lymphoid Progenitor (HTLP) injection; The HTLP cell suspension will be injected intravenously at the time of UCB HSCT on D0

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of grade III-IV graft-versus-host disease (GvHD)	according to Glucksberg grading system, to define toxicity	100 Days following HSCT
CD4 + T cells analysis	Efficacy defined by the presence of >50/μl CD4+ CD3+ TCRαβ+ T cells at 2 consecutive measures < within 4 months post HSCT.	100 days following HSCT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time course of T cell immune reconstitution	time needed to exceed a count of 100 naive CD4+ and >100 total CD8+ cells per μL	Month 1, 2, 3, 4, 5, 6 and 12 post-transplantation
Time to hematologic engraftment	Time to ANC > 0.5G/L with platelets > 20G/L	Up to 24 months post-transplantation
Numbers of neutrophils, platelets and red blood cell transfusions		Month 1,2, 3, 6 and 12 post -transplantation
time course of reconstitution of the different T-cell subpopulations	by immunophenotyping (flow cytometry analysis)	Month 1,2, 3, 6 and 12 post -transplantation
Presence of Recent thymic emigrants (RTEs)	by immunophenotyping (flow cytometry analysis)	Month 1,2, 3, 6 and 12 post -transplantation
Tregs numbers	by immunophenotyping (flow cytometry analysis)	Month 1,2, 3, 6 and 12 post -transplantation
B-cell reconstitution	number and phenotype for naïve IgD+CD27-, marginal zone IgD+CD27+, switched memory IgD-CD27+, and IgD-CD27- cells	Month 6 and 12 post -transplantation
Immunoglobulin levels	focus on time needed for cessation of intravenously IgG replacement therapy	Month 6 and 12 post -transplantation
Reconstitution of the NK cell	compartment (CD3-CD56dimCD16bright)	Month 6 and 12 post -transplantation
Assessment of engraftment of each UCB unit over time by hematological monitoring and chimerism analysis on neutrophils, T, B, NK, pDC and macrophages at 1, 2, 3, 6 and 12 months following HSCT	To assess engraftment of each UCB unit over time by hematological monitoring and chimerism analysis on neutrophils, T, B, NK, pDC and macrophages at 1, 2, 3, 6 and 12 months following HSCT.	at 1, 2, 3, 6 and 12 months following HSCT.
the graft failure/rejection rate	detected by hematological monitoring of each UCB unit	3 months following HSCT
Cumulative incidence of infections		3, 6 and 12 months post- transplantation
Cumulative incidence of acute and chronic episodes of GVHD and their grade	according to Glucksgberg GvHD staging	3, 6, 12 and 24 months post-transplantation
relapse rate		2 years post -transplantation
overall survival		2 years post -transplantation
Disease-free survival		2 years post -transplantation
Progression-free survival		2 years post -transplantation

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Olivier HERMINE, PhD & MD, Assistance Publique - Hôpitaux de Paris; Study Director: Elisa MAGRIN, MD, Département de Biothérapie : Hôpital Necker Enfants malades

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2022
• Primary Completion (Anticipated): May 1, 2024
• Study Completion (Anticipated): February 1, 2026

Study Registration Dates

• First Submitted: November 30, 2020
• First Submitted That Met QC Criteria: January 12, 2021
• First Posted (Actual): January 13, 2021

Study Record Updates

• Last Update Posted (Actual): November 1, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: minimal residual disease; acute myeloid leukemia; hematologic malignancies; umbilical cord blood transplantation; human T Lymphoid Progenitor
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms
• Other Study ID Numbers: APHP191116; 2019-004883-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No